1-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine hydrobromide, also known as vortioxetine hydrobromide, is a multimodal serotonergic compound currently in clinical development for major depressive disorder and generalized anxiety disorder. It has been disclosed in the art that the compound shows antagonistic properties at 5-HT3A and 5-HT7, receptors, partial agonistic properties at 5-HT1B receptors, agonistic properties at 5-HT1A receptors and potent serotonin reuptake inhibition via inhibition of the serotonin transporter (SERT). Vortioxetine hydrobromide is represented by the following general formula A:

WO 2003/029232 A1 discloses vortioxetine and pharmaceutically acceptable salts thereof per se as well as pharmaceutical compositions comprising the same. However, only a concrete example for preparing vortioxetine free base is given in said application.
WO 2007/144005 A1 discloses crystalline vortioxetine base and a variety of crystalline vortioxetine salts, comprising polymorphs of vortioxetine hydrobromide as well as a hemihydrate and an ethyl acetate solvate thereof, and crystalline vortioxetine hydrochloride and a monohydrate thereof. Crystalline vortioxetine mesylate, hydrogenfumarate, hydrogenmaleate, mesohydrogentartrate, L-(+)-hydrogentartrate, D-(−)-hydrogentartrate, hydrogen sulphate, dihydrogenphosphate and nitrate are also disclosed.
WO 2010/094285 A1 discloses an isopropanol solvate of vortioxetine hydrobromide as well as a process for the purification of vortioxetine and pharmaceutically acceptable salts thereof.
Polymorphism is a phenomenon relating to the occurrence of different crystalline forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, XRPD pattern and FTIR spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct advantageous physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, morphology or bioavailability. In addition the preparation process of a crystalline form plays an important role in the development of an active pharmaceutical ingredient. It is essential that the crystallization process is robust and reliably produces the desired crystalline form in polymorphically pure form.
The acceptable amount of solvents in an active pharmaceutical ingredient is strictly regulated e.g. by the ICH guideline for residual solvents. Solvates of vortioxetine hydrobromide such as e.g. the ethyl acetate solvate of WO 2007/144005 A1 and the isopropanol solvate of WO 2010/094285 A1 are no suitable crystalline forms for the preparation of a medicament as they clearly exceed the recommended solvent amount for class 3 solvents. In summary, solvates of vortioxetine hydrobromide know in the art are no suitable forms for the preparation of a medicament due to the strict limits for residual solvents in an active pharmaceutical ingredient.
In addition, an active pharmaceutical ingredient is preferably non-hygroscopic in order to ensure the chemical and physical quality during the storage of the active substance itself and during the shelf-life of a solid finished dosage form containing the active substance without the need of special and expensive packaging. However, according to the presented data in WO 2007/144005 A1 the gamma form and the hemihydrate of vortioxetine hydrobromide disclosed in WO 2007/144005 A1 significantly take up water at increased relative humidities and are therefore not favored for the preparation of a solid medicament.
Furthermore the bioavailability of a compound intended to be administered orally, is dependent on the compounds solubility as well as the compounds permeability according to the biopharmaceutical classification system (BCS). Therefore a drug substance having high solubility which is consequently highly bioavailable is desired.
Finally the crystalline forms alpha, beta and the ethyl acetate solvate of WO 2007/144005 A1 as well as the crystalline form gamma and the hemihydrate of WO 2007/144005 A1 are difficult to make in a reliable manner because these forms are obtained via crystallizations from the same solvent systems. As the ethyl acetate solvate and the polymorphs alpha and beta are all obtained via crystallizations from ethyl acetate and the form gamma and the hemihydrate are both obtained via crystallizations from water the production processes are especially critical and sensitive because the single crystalline forms are only obtained in pure form in a quite narrow range of critical parameters, such as the crystallization temperature, the concentration and the stirring time as described in the concrete examples 4a, 4c, 4e, 4g and 4i of WO 2007/144005 A1.
The technical problem underlying the present invention is to circumvent the drawbacks of the known crystalline forms of vortioxetine hydrobromide disclosed in the state of the art such as toxicity issues of solvates, stability issues due to water uptake, bioavailability issues due to limited solubility and preparation issues due to similar crystallization processes by providing a non-solvated crystalline form of vortioxetine hydrobromide which is non-hygroscopic, shows high solubility and is obtained in polymorphically pure form in an easy and reliable manner.